The etiology of Meniere's disease has not yet been settled. However, as is well known in the art, the characteristic histo-pathological feature of Meniere's disease is endolymphatic hydrops considering from the histological observation of autopsy specimens from patients with Meniere's disease. It is believed that such endolymphatic hydrops may be induced by the accumulation of endolymphatic fluid due to an aberrant water-metabolism in the inner ear, such as an excess production and/or an impaired absorption of endolymphatic fluid, leading one or more of conditions associated with Meniere's disease, for example, tinnitus, hearing disorder, vertigo, ear fullness or the like. Therefore, it may be understood that decompressing the endolymphatic hydrops may lead the treatment of Meniere's disease.
Most of saccharides and sugar alcohols exhibit an osmotic effect after the administration and have been used as osmotic diuretics or osmotic pressure decreasing agents. As the agents having a dehydrating activity due to the osmotic effect, there are known sorbitol, mannitol, etc., which have a cathartic effect, as well as mannitol, glycerol, etc., which have a diuretic effect. Since the histo-pathological feature of Meniere's disease is endolymphatic hydrops, it appears that hydrops would be decompressed by the dehydrating action. Namely, said agents which produce an osmotic gradient between endolymphatic and perilymphatic compartments are thought to exert a dehydratic effect upon the scala media, and also induce the decompression and/or the collapse of the volume of endolymphatic space and reveal the decompressing effect on endolymphatic hydrops.
Actually, some of saccharides or sugar alcohols as the osmotic diuretics are used for diagnosis of Meniere's disease (cf. Ichiro Kirikae, Otorhinolaryngology, P174, L34-P175, L2; Non-patent Reference 1). During the test, the hearing improvement was observed due to the osmotic diuretics (cf. Atsushi Komatsuzaki, Client 21, P368, right column L23-24; Non-patent Reference 2). Considering these facts, various trials have been made to develop the therapeutic agents.
Contrary to what might be expected, all of trials failed finally, and the riddle for such failure remained unsolved. Angelborg C. et al reported that the improvement of the hearing could only be observed in the half or more cases of the group administered with glycerol (cf. Non-patent Reference 3, P201, Table 1). When, however, guinea pigs orally received glycerol at 2.8 g/kg, the collapse was observed in the normal ear 2 hours after the administration, and the mild hydrops were observed 6 hours after (cf. Non-patent Reference 4); namely, rebound phenomenon was observed morphologically. These results can histologically support the so-called “rebound phenomenon” which is observed in the glycerol test for diagnosis of Meniere's disease as a temporary improvement of hearing 2 hours after the administration and subsequent deterioration 6 hours after (cf. Non-patent Reference 5). Because of rebound phenomenon, glycerol is currently not used as a therapeutic agent in Japan.
Since the 1990s, the presence of water channels was successively confirmed in several organs. In the inner ear having a relatively similar tissue structure to the kidney, the study was developed for elucidation of the mechanisms of water homeostasis, the production and absorption of fluid in inner ear, and the presence of aquaporin (water channel protein) in the inner ear was confirmed (cf. Non-patent Reference 6). Recently, the arginine vasopressin-aquaporin 2 system has widely noticed as the one associated with the water metabolism in the inner ear (cf. Non-patent Reference 7).
However, the systemic administration of OPC 31260 as the vasopressin type II receptor antagonist did not reveal the decompression effect on endolymphatic hydrops as originally expected and rather resulted in formation of endolymphatic hydrops in the normal ear (cf. Non-patent Reference 8). This was found to be due to the dehydration caused by the potent diuretic effect, i.e. the increase of arginine vasopressin (AVP) as the antidiuretic hormone (ADH) in plasma. As understood from the above, many trial-and-error investigations have been made up to this time, but none of them led to the successful outcome applicable to the clinical use.
It was reported that the AVP level is clinically enhanced at an acute phase in patients with Meniere's disease (cf. Non-patent Reference 9). This result is coincident with an epidemiological fact that Meniere's disease is prevalent under stress. Also, the continuous administration of AVP at 1 mU/kg/minute by the aid of a mini-pump subcutaneously to guinea pigs of normal Prayer's reflex apparently produced endolymphatic hydrops (cf. Non-patent Reference 10). As shown in Table 1 below, the plasma AVP level is elevated in proportion to the administration amount of AVP, whereby the area of scala media is increased histologically (formation of endolymphatic hydrops). When AVP is successively administered at 1 mu/kg the serum AVP level is elevated to several times higher than that of normal human plasma AVP level (nearly equal to the serum AVP level at an acute phase in a patient with Meniere's disease), which is at serious risk (cf. Non-patent Reference 10). For treatment of Meniere's disease, special care is needed not to cause the elevation of the AVP level by stress, dehydration or the like.
TABLE 1Increase ratio (%)of the cross-sectional area ofAgentPlasma AVPthe scala mediaSaline1.2 ± 0.55.2 ± 1.7AVP 0.2 mU2.2 ± 0.44.4 ± 0.7AVP 0.4 mU3.5 ± 1.810.4 ± 1.8 AVP 1.0 mU14.0 ± 3.9 17.4 ± 7.9 (The present inventors, Hearing Res. 2000; Non-patent Reference 10)    Administration rate of AVP: mU/kg/min    Unit of plasma AVP: pg/ml
The upper limit of the plasma AVP level for a normal subject is 3.5 pg/ml.
As predicted from the fact that saccharides or sugar alcohols are used as osmotic pressure reducing agents, those basically induce an osmotic gradient in the digestive organ and develop gastrointestinal disorders such as diarrhea when administered orally at a high dose at one time. Even severe diarrhea, which cannot be treated by common gastrointestinal agents, arises frequently. In case of severe diarrhea, it is reported that the dehydration is brought about sequentially and the level of AVP as antidiuretic hormone is elevated to 10-15 times (cf. Non-patent Reference 11). Since elevated AVP level may induce endolymphatic hydrops as stated above, it is conceived that the endolymphatic hydrops decompression effect of sacchrides or sugar alcohols may be countered by the dehydration following diarrhea, unless the diarrhea induced by them is successfully inhibited. Accordingly, careful attention should be taken not to aggravate gastrointestinal disorders such as diarrhea, when patients with Meniere's disease are treated with saccharides or sugar alcohols,
Patent Reference 1 discloses a pharmaceutical composition for treating Meniere's disease comprising a tetrose such as erythritol as the sole active ingredient. Erythritol is advantageous in having a favorable flavor, but it is reported that transient severe diarrhea was induced on taking a large amount of a sports drink containing erythritol as a low-calorie sweetener within a short period of time. Therefore, the therapeutic effect of erythritol for Meniere's disease can be hardly expected without inhibiting diarrhea,
The sugar alcohol currently on the clinical use as a therapeutic agent for Meniere's disease is isosorbide (1,2:3,6-dianhydro-D-sorbitol). Its cathartic effect is relatively weak in a clinical practice but it has a characteristic bitter taste which remains in oral cavity for a long time. In addition, it has to be administered at such a high dose as 30 ml or more each three times per day. Because of these reasons, it causes poor compliance for patients leading to give up taking said substance. Also, it was inconvenient that the dosage form is a solution and the recipients must carry such large volume bottles as 500 ml due to sanitary issues.
In addition, glycerol as a triose exerts its effect about 2 hours after the oral administration, meanwhile isosorbide as a hexose takes as long time as 6 hours or so until exertion of its effect (cf. Non-patent Reference 12).    Patent Reference 1: JP-A-11-180863;    Non-patent Reference 1: Ichiro Kirikae, Otorhinolaryngology;    Non-patent Reference 2: Atsushi Komathuzaki, Client 21;    Non-patent Reference 3: Angelborg, C. et al.: Hyperosmotic solutions and hearing in Meniere's disease. Am. J. Otol. 3: 200-2 (1982);    Non-patent Reference 4: Takeda, T. et al.: The rebound phenomenon of glycerol-induced changes in the endolymphatic space. Acta Otolaryngol. 119: 341-4 (1999);    Non-patent Reference 5: Matsubara, H. et al.: Rebound phenomenon in glycerol test. Acta Otolaryngol. Suppl. 419: 115-22 (1984);    Non-patent Reference 6: Sawada, S. et al.: Aquaporin-1 (AQP1) is expressed in the stria vascularis of rat cochlea. Hear. Res. 181:15-9 (2003);    Non-patent Reference 7: Sawada, S. et al.: Aquaporin-2 regulation by vasopressin in the rat inner ear. Neuroreport. 13: 1127-9 (2002);    Non-patent Reference 8: Takeda, T. et al.: The effects of V2 antagonist (OPC-31260) on endolymphatic hydrops. Hear. Res. 183: 9-18 (2003);    Non-patent Reference 9: Takeda, T. et al.: Antidiuretic hormone (ADH) and endolymphatic hydrops. Acta Otolaryngol. Suppl. 519: 219-22 (1995);    Non-patent Reference 10: Takeda, T. et al.: Endolymphatic hydrops induced by chronic administration of vasopressin. Hear. Res. 140:1-6 (2000);    Non-patent Reference 11: Safwate A. et al.: Renin-aldosterone system and arginine vasopressin in diarrhoeic calves. Br. Vet. J. 147:533-7 (1991);    Non-patent Reference 12: Kakigi, A. et al.: Time course of dehydratic effects of isosorbide on experimentally induced endolymphatic hydrops in guinea pigs. ORL J. Otorhinolaryngol. Relat. Spec. 66:291-296 (2004).